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WO1989012070A1 - Glycosaminoglycan salts, processes for the preparation thereof and pharmaceutical compositions containing them - Google Patents

Glycosaminoglycan salts, processes for the preparation thereof and pharmaceutical compositions containing them Download PDF

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Publication number
WO1989012070A1
WO1989012070A1 PCT/EP1989/000605 EP8900605W WO8912070A1 WO 1989012070 A1 WO1989012070 A1 WO 1989012070A1 EP 8900605 W EP8900605 W EP 8900605W WO 8912070 A1 WO8912070 A1 WO 8912070A1
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WO
WIPO (PCT)
Prior art keywords
butyl
salts
carbonate
methyl
ester
Prior art date
Application number
PCT/EP1989/000605
Other languages
English (en)
French (fr)
Inventor
Alma Dal Pozzo
Maurizio Acquasaliente
Giancarlo Sportoletti
Monique Sarret
Paolo Ferruti
Francesco De Santis
Original Assignee
Italfarmaco S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from IT20854/88A external-priority patent/IT1219704B/it
Priority claimed from IT8947985A external-priority patent/IT1231915B/it
Application filed by Italfarmaco S.P.A. filed Critical Italfarmaco S.P.A.
Priority to DE1989906364 priority Critical patent/DE423151T1/de
Priority to KR1019900700235A priority patent/KR920700232A/ko
Priority to SU894894096A priority patent/RU2070879C1/ru
Priority to AT89906364T priority patent/ATE94883T1/de
Priority to IN435/MAS/89A priority patent/IN169470B/en
Publication of WO1989012070A1 publication Critical patent/WO1989012070A1/en
Priority to NO90905146A priority patent/NO905146L/no
Priority to FI905934A priority patent/FI905934A0/fi
Priority to DK286190A priority patent/DK286190D0/da

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0069—Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof

Definitions

  • the present invention refers to glycosaminoglycan salts able to induce therapeutically effective blood levels of the glycosaminoglycanic polyanion even when administered orally or rectally.
  • Proteoglycans are macromolecules characterized by a proteic core to which different polysaccharides are covalenty bound. They differentiate for the nature of the proteins and that of the saccharidic side chains and constitute the major part of some mammalian. tissues.
  • suitable hydrolytic methods e.g. by means of proteases
  • the glycosaminoglycans known as chondroitin-4- or
  • 6-sulfate, heparan sulfate, heparin, dermatan sulfate, hyaluronic acid etc. characterized, in each single family, by polydispersion of molecular weight and also by heterogenity in the saccharidic compositions, are thus obtained, also industrially.
  • glycosaminoglycans Due to their highly hydrophilic, polyanionic nature, glycosaminoglycans are able to interact with various chemical species, such as divalent cations or plasmatic basic proteins, often aspecifically and sometimes (such as in the case of the heparin - anti-thrombin III complex or of the dermatan sulfate - cofactor III complex) with a certain specificity, whose degree is higher or lower according to the ligand or to the binding agent.
  • various chemical species such as divalent cations or plasmatic basic proteins
  • glycosaminoglycans are interesting therapeutic means, because they allow to control pathological conditions wherein either the activation or the inhibition, of certain plasma factors (such as anti-thrombin III or the activated factor X) are highly useful.
  • glycosaminoglycans used for the preparation of the salts of the invention are the following:
  • Heparin is extracted from tissues of different origin: bovine or porcine intestinal mucosa, lung etc. Chemically heparin, as well as its fractions or fragments, is a mixture having polydispersed molecular weight ranging from 1.000 to 30.000 D.
  • heparin Under the biological profile, heparin itself, its fragments and fractions show different pharmacological activities, particularly anticoagulant, anti-thrombotic, antiangiogenetic and antilipemic activities. Said activities are connected with the ability of developing interactions with different factors either plasmatic or extra-plasmatic (anti-thrombin III, activated factor X, heparin cofactor II, plasminogen activator, lipoprotein- lipase in addition to platelet factors). According to the use of heparin as such or of its fragments or fractions (having low molecular weight: 3500-9000 D), one mechanism of action may overcome anotherone or a more or less prolonged pharmacokinetics may result.
  • the salts of these polyanions most frequently used in human therapy are the sodium, calcium or magnesium salts .
  • Dermatan sulfate may be obtained from mammalian tissues such as skin, bowels, tendons etc. by means of enzymatic and controlled chemical hydrolysis.
  • chondroitin sulfate B It is also known as chondroitin sulfate B and shows an anti-thrombotic activity unrelated to the anticoagulant one, so as to be considered a therapeutic agent safer than heparin.
  • the anti-thrombotic activity seems to be due, according to the present knowledge, to the ability of catalyzing the reaction between heparin cofactor III and thrombin with consequent inactivation of the latter.
  • the used salts are the sodium and calcium salts .
  • Heparan sulfate is obtainable from connective tissues such as lungs, basal membranes, walls of blood vessels, pancreas etc.
  • the used salt is an inorganic salt, such as sodium, calcium or magnesium salts.
  • a particular family of glycosaminoglycans is that of the "supersulfatated" derivatives, obtained by sulfatation of the above reported different products (having or not low molecular weight), disclosed in EP 116801. Said derivatives are endowed with low anticoagulant activity, average anti - Xa activity and an anti-thrombotic activity comparable to that of the starting glycosaminoglycan. Also in this case the used form is the sodium or calcium salt.
  • Another family of chemically modified glycosaminoglycans is that obtained by controlled N-desulfatation (with more or less high N-desulfatation degrees) and subsequent succinylation, as disclosed in Italian patents N. 1.140.999 and 1.169.888 and in U.S. patent 3.118.816.
  • Said derivatives in form of sodium or calcium salts, show a reduced anticoagulant activity and good lipasemic and anti-thrombotic activities.
  • the inorganic salts of the above mentioned glycosaminoglycans may be administered in form of suitable formulations by the systemic route (intravenously, by infusion, subcutaneously etc.) to experimental animals and to humans, showing a marked anti-thrombotic action (particularly venous), which is not noticed when their administration is carried out by the oral route, because of an insufficient bioavailabilty of the active principles.
  • Said insufficient oral absorption involves a remarkable limitation for the preventive therapies, carried out for long periods.
  • R 1 , R 2 , R 3 and R 4 which are the same or different, represent hydrogen; linear or branched alkyl; cycloalkyl; aralkyl; or R 1 and
  • R 2 respectively R 3 and R 4 , together with the nitrogen atom to which they are bound, form a 5 - or 6 - membered heterocyclic ring optionally containing other hetero-atoms ;
  • R 5 and R 6 which are the same or different, represent hydrogen, C 1 -C 4 alkyl or aryl;
  • R 7 and R 8 which are the same or different, represent hydrogen or C 1 -C 4 alkyl; n and m, which are the same or different, are integers 1 to 4 inclusive; X represents one of the following groups:
  • R 9 and R 10 represent hydrogen or C 1 -C 4 alkyl , whereas p is an integer 1 to 6 inclusive; q is an integer 1 to 4 inclusive; r is an integer 1 to 5 inclusive.
  • the present invention also relates to the corresponding bases of the cations of formula I as well as to the inorganic or organic acid salts thereof (such as, for example, the hydrohalogen, sulfuric, phoshoric, carbonic, nitric, formic, acetic, oxalic, maleic, citric, tartaric acids), to the processes for the preparation of the salts of cations I with glycosaminoglycan polyanions; to the pharmaceutical compositions containing one or more salts of glycosaminoglycans with the cations of formula I.
  • the inorganic or organic acid salts thereof such as, for example, the hydrohalogen, sulfuric, phoshoric, carbonic, nitric, formic, acetic, oxalic, maleic, citric, tartaric acids
  • R 1 - R 6 , X, n and m have the above mentioned meanings
  • dialkylcarbonates carboxylic acid esters, ureas, carbamates, dicarboxylic acid esters or diol esters, diamides, ester-amides and the like.
  • R 1 and R 2 respectively R 3 and R 4 form together with the respective nitrogen atom two equal heterocyclic rings
  • the corresponding aminoalcohols are reacted with phosgene in an about 2:1 molar ratio,in inert solvents such as arenes or ethers or halogenated hydrocarbons, at temperatures from -10o to + 30 oC, preferably at about 0oC.
  • the reaction mixture is shaken with an aqueous solution of sodium or potassium hydrogencarbonate or carbonate sufficient to neutralize the formed hydrochloric acid; the organic phase is dried and evaporated to dryness.
  • the obtained products are optionally purified by chromatography.
  • phosgene can be replaced by N,N'-carbonyl-diiimidazole; in this istance the reaction is carried out in the presence of small amounts of the sodium aminoalkoxide previously prepared by reacting metal sodium with the aminoalcohol, at temperatures from 0o to 50oC, preferably at room temperature. In this case the product is recovered by washing the organic solution with water only.
  • R 1 , R 2 , R 5 have the above mentioned meanings
  • an ⁇ , ⁇ -unsaturated acid reactive derivative for example the chloride or the anhydride
  • the reaction is suitably carried out in inert solvents (halogenated hydrocarbons, arenes, ethers) and in the presence of a tertiary base ( triethylamine, pyridine) as the acid binding agent.
  • the resulting ester is then reacted with a R 3 R 4 NH amine excess, at temperatures from 0o to 40oC, preferably at room temperature, to obtain the addition of the same amine to the reactive double bond.
  • R 1 R 2 NH dialkylamine is reacted with an R 5 -CHO aldehyde, in the presence of potassium carbonate, in aqueous medium and at room temperature.
  • the reaction product is reacted with an R 5 -CHO aldehyde, in the presence of potassium carbonate, in aqueous medium and at room temperature.
  • the salts of glycosaminoglycan polyanions and thecations of formula la, according to the invention, can be obtained: a) by subjecting aqueous solutions of glycosaminoglycan sodium and calcium salts to chromotography on resins, at T ⁇ 7oC, to partially or completely remove sodium and calcium ions. The eluates are treated either with bases la or with hyrtroxides of the cations I, in which
  • R 7 and R 8 are C 1 -C 4 alkyl, in the desired stoichiometrie ratio, to obtain either "neutral" salts or salts still containing an anion excess,which possibly can be neutralized with different cations, or a cation excess which can be neutralized with different anions; b) by subjecting to diafiltration aqueous solutions of glycosaminoglycans sodium salts and of salts of the cations of formula I with inorganic acids, particularly hydrohalogen acids.
  • the final salt is suitably recovered by freeze-drying.
  • glycosaminoglycans and derivatives thereof and the following tests were used: 1. Glycosaminoglycans (GAG):
  • Anti-Xa activity 72 units/mg (chromogens).
  • Anti-coagulant activity 20 I.U./mg (PRODUCT P4).
  • Anti-Xa activity 60 units/mg (chromogens).
  • Anti-coagulant activity 15 I.U./mg (PRODUCT P5).
  • glycosaminoglycans such as heparan, low molecular weight heparin and heparan sulfate.
  • the used method consists in the ex vivo evaluation of the factor Xa inhibition after intraduodenal administration in the rat, rabbit or dog of the compound under exam in comparison with the starting glycosaminoglycan salified with inorganic ions (sodium, calcium).
  • the used determination method is the above described chromogenic method (COATEST R ); it provides spectrophotometric values which are converted into blood concentrations (meg/ml) of glycosaminoglycans, obtained by comparison with a calibration curve calculated with the same glycosaminoglycan in form of sodium salt, added in vitro to the plasma. Said calibration curve is obtained for each kind of used glycosaminoglycan. 2.4. Evaluation of the in vivo antithrombotic activity for the glycosaminoglycans not endowed with anti-Xa activity, such as dermatan sulfate, after intraduodenal administration in the rat (thrombosis model of Reyers et al. - Thromb. Res. Vol. 8, 669, 1980, consisting in the ligation of the lower vena cava in order to induce stasis and then thrombosis).
  • EXAMPLE 1 preparation of bis-N,N-dialkylamino-alkylene carbonates (X: -O-CO-O-) A flask containing 500 ml of toluene was weighted, then ice-cooled; gaseous phosgene was slowly bubbled therein (for about 1 hour) until the weight corresponding to 0,55 mole was reached.
  • N,N-dialkylamino-alcohol corresponding to the desired final product (1 mole) was added under stirring at 0oC and the solution was left to stand for 2 hours; then it was shaken with a cool diluted aqueous solution of 0,58 mole of K 2 CO 3 , then with water, finally it was dried over Na 2 SO 4 . Solvent was evaporated off to leave residues consisting of the final products in form of pale yellow or colorless oils, in 90% average yields. The products can be purified from any traces of the starting reactives by column chromatography (silica gel 60, 70-230 mesh, eluent: benzene /tetrahydrofuran 60:40).
  • the mixture was diluted with 250 ml more of tetrahydrofuran and N,N-carbonyl-diimidazole (0,55 mole) was added, under cooling, if necessary, to maintain the reaction mixture to room temperature. After 1 hour stirring, the solvent was removed under vacuum and the residue was taken up into chloroform until complete dissolution. The chloroform solution was washed with the same volume of water and evaporated to dryness to obtain an oily residue consisting of the final product, in an about 95% yield on theory. The final product can further be purified by chromatography, as described in Example 1.
  • EXAMPLE 3 preparation of bis-N,N-dialkylamino-alkylene esters (X: -O-CO-; both n and m >1 An N,N-dialkylamino-alcohol corresponding to the desired final product (0,05 mole) and triethylamine (0,55 mole) were dissolved in 500 ml of anhydrous methylene chloride. The solution was cooled to 0o-5oC, said temperature being maintained during the whole reaction time. 0,55 mole of acryloyl chloride dissolved in 150 ml of methylene chloride was slowly added to the reaction flask, under stirring. At the end of the addition the reaction was left to proceed until completion for 1 hour, under stirring.
  • N,N-dialkylamine corresponding to the desired final product (0.5 mole) and potassium carbonate (0.05 mole) were suspended into 1 liter of distilled water at room temperature.
  • the corresponding aldehyde (5 moles) was added under strong stirring to the suspension, which was reacted for 24 hours. After that, the crude product was extracted with chloroform, washing then the chloroform solution with the appropriate water amount (Solution A).
  • dialkyl-glycine corresponding to the desired final product (0.5 mole) was dissolved in 500 ml of chloroform with pyridine (0.5 mole) and dicyclohexylcarbodiimide (0.5 mole) was added to the solution; the mixture was kept under stirring at room temperature for 1 hour (Solution B).
  • the solution was cooled to 0o-5oC and a solution of acryloyl chloride (0.55 mole) in 150 ml of methylene chloride was slowly added, under stirring, keeping temperature at about 0oC. After that the mixture was kept under stirring for 1 hour, then it was filtered and the filtered solution was washed with water, with a saturated hydrogencarbonate solution, then again with water; then the procedure described in Example 3 was carried out.
  • N,N-dialkylamino-alkylene-aerylamide was obtained in a 95% yield.
  • the transformation into the desired N,N-dialkylamino-alkylene-amides (in quantitative yields) takes place as described in Example 3.
  • EXAMPLE 7 preparation of bis-N,N—dialkylamino-alkylene- -ureas (X: -HN-CO-NH-) The procedure of Example 2 was followed, using N,N-dialkylamino-amines instead of the corresponding amino-alcohols. Yields of 95-100% on theory.
  • EXAMPLE 8 salification of heparin (PI) with bis-N,N- -dibutyl-ethylene carbonate (Table 1: base 2; Table 2 : salt 2a), by direct salification of the glycosaminoglycan acid
  • EXAMPLE 10 salification of heparin (PI) with bis-N,N-dibutyl-ethylene-carbonate (Table 1: base 2; Table 2: salt 2a) by shifting the salification equilibrium with membranes 7 g of heparin (product P1, item 1.1 of the Preliminary Remarks) were dissolved in 50 ml of distilled water and 7 g of bis-N,N-dibutyl-ethylene-carbonate (2) were added thereto, in a continuous diafiltration system provided with a cellulose acetate membrane (or polyester, teflon, polyamide or polyurethane membrane) with cut-off from 200 to 1.000 D (preferably 600 D) : when 200 ml of dialfiltration product were reached, further 7 g of bis-N,N-dibutyl-ethylene-carbonate were added and diafiltration was repeated until absence of sodium in the diafiltrate.
  • the plasma levels are detected at 30' from the administration and are expressed as mean value ⁇ E.S. (animals: S.D. Charles River rats, weighing about 300 g, fasted, 5 animals per group, under anesthesia; or N.Z. rabbits coming from Bettinardi, about 2 Kg weight, fasted, under anesthesia, 3 animals per group).
  • ⁇ E.S. animals: S.D. Charles River rats, weighing about 300 g, fasted, 5 animals per group, under anesthesia; or N.Z. rabbits coming from Bettinardi, about 2 Kg weight, fasted, under anesthesia, 3 animals per group.
  • the absorptions are 1.4 to 450 times higher than those of the corresponding glycosaminoglycan (for the P4 derivative the absorption is considered zero since, under the used experimental conditions, it could not be dosed in a statistically certain way).
  • Said absorptions may be improved using suitable carriers instead of the aqueous solution, as the data reported in Table 3 show, where
  • the derivative 2a has been administered i.d. in the dog with duodenal fistula at the dose of 100 mg/Kg. Beagle dogs coming from Allevamento Alserio weighing 10-12 kg (3 animals/group) have been used. In the Table 6, the heparin plasma levels, measured as decribed in item 2.4, at different times after the i.d. treatment, are reported. EXAMPLE 15
  • the thrombus evaluation is carried out after a two-hours stasis.
  • the present invention also relates to all the industrially applicable aspects connected with the use of salts of glycosaminoglycans with cations of formula I as therapeutic agents. Therefore, an essential object of the invention is provided by pharmaceutical compositions containing as the active ingredient therapeutically effective amounts of said salts together with conventional excipients and carriers.
  • compositions are tablets, sugar-coated pills, syrups, vials for oral, intramuscular or intravenous administrations and suppositories, containing 5 to 500 mg of the active ingredient, to be administered 1 to 3 times a day.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
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  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Polymers & Plastics (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
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  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
PCT/EP1989/000605 1988-06-03 1989-05-30 Glycosaminoglycan salts, processes for the preparation thereof and pharmaceutical compositions containing them WO1989012070A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
DE1989906364 DE423151T1 (de) 1988-06-03 1989-05-30 Salze von glykosaminoglykanen, verfahren zu ihrer herstellung und diese salze enthaltende pharmazeutische zusammensetzungen.
KR1019900700235A KR920700232A (ko) 1988-06-03 1989-05-30 글리코사미노글리칸 염류, 그 제조방법 및 이를 함유하는 제약 조성물
SU894894096A RU2070879C1 (ru) 1988-06-03 1989-05-30 Соли гликозаминогликанов и гликозаминогликаны
AT89906364T ATE94883T1 (de) 1988-06-03 1989-05-30 Salze von glykosaminoglykanen, verfahren zu ihrer herstellung und diese salze enthaltende pharmazeutische zusammensetzungen.
IN435/MAS/89A IN169470B (it) 1988-06-03 1989-06-02
NO90905146A NO905146L (no) 1988-06-03 1990-11-28 Fremgangsmaate ved fremstilling av glykosaminoglykansalter.
FI905934A FI905934A0 (fi) 1988-06-03 1990-11-30 Glykosaminoglykansalter, foerfaranden foer framstaellning av dessa och farmaceutiska sammansaettningar som innehaoller dem.
DK286190A DK286190D0 (da) 1988-06-03 1990-11-30 Glycosaminoglycansalte, fremgangsmaader til fremstilling heraf og farmaceutiske midler indeholdende dem

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IT20854A/88 1988-06-03
IT20854/88A IT1219704B (it) 1988-06-03 1988-06-03 Sali di glicosaminoglicani,procedimento per la loro preparazione e relative composizioni farmaceutiche
IT47985A/89 1989-05-24
IT8947985A IT1231915B (it) 1989-05-24 1989-05-24 Sali di glicosaminoglicani, procedimento per la loro preparazione e relative composizioni farmaceutiche

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WO1989012070A1 true WO1989012070A1 (en) 1989-12-14

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US (1) US5264425A (it)
EP (1) EP0423151B1 (it)
JP (1) JPH04500377A (it)
KR (1) KR920700232A (it)
AU (1) AU630359B2 (it)
CA (1) CA1335375C (it)
DE (1) DE68909412T2 (it)
DK (1) DK286190D0 (it)
HU (1) HU208029B (it)
IN (1) IN169470B (it)
MC (1) MC2098A1 (it)
NZ (1) NZ229403A (it)
WO (1) WO1989012070A1 (it)

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EP0485748A2 (en) * 1990-11-13 1992-05-20 ALFA WASSERMANN S.p.A. Salts of glycosaminoglycans with esters of aminoacids, preparation thereof and pharmaceutical formulations containing them
US5145841A (en) * 1987-03-19 1992-09-08 Arthropharm Pty. Limited Anti-inflammatory compounds and compositions
US5164378A (en) * 1989-11-24 1992-11-17 Iketon Farmaceutici, S.R.L. Supersulfated heparins
WO1995023128A1 (en) * 1994-02-28 1995-08-31 Italfarmaco S.P.A. Diesters of carbonic acid endowed with antiviral and anti-inflammatory activity
US5668116A (en) * 1987-03-19 1997-09-16 Anthropharm Pty. Limited Anti-inflammatory compounds and compositions
WO2022168085A1 (en) * 2021-02-02 2022-08-11 Ramot At Tel-Aviv University Ltd. Lipids suitable for nucleic acid delivery

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US20040087543A1 (en) * 2002-04-25 2004-05-06 Zachary Shriver Methods and products for mucosal delivery
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US9139876B1 (en) 2007-05-03 2015-09-22 Momenta Pharmacueticals, Inc. Method of analyzing a preparation of a low molecular weight heparin
US8592393B2 (en) * 2007-11-02 2013-11-26 Momenta Pharmaceuticals, Inc. Polysaccharide compositions and methods of use for the treatment and prevention of disorders associated with progenitor cell mobilization
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US8569262B2 (en) 2007-11-02 2013-10-29 Momenta Pharmaceuticals, Inc. Polysaccharide compositions and methods of use for the treatment and prevention of disorders associated with progenitor cell mobilization
US8435795B2 (en) * 2010-01-19 2013-05-07 Momenta Pharmaceuticals, Inc. Evaluating heparin preparations
EP2558506B1 (en) 2010-04-16 2019-06-26 Momenta Pharmaceuticals, Inc. Tissue targeting
CN103096870B (zh) 2010-06-17 2017-04-19 动量制药公司 调节毛发生长的方法和组合物
US9068957B2 (en) 2011-02-21 2015-06-30 Momenta Pharmaceuticals, Inc. Evaluating heparin preparations
AU2014274377A1 (en) 2013-05-28 2015-11-12 Momenta Pharmaceuticals, Inc. Pharmaceutical compositions

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MC2098A1 (fr) 1991-02-15
DE68909412T2 (de) 1994-02-03
DE68909412D1 (de) 1993-10-28
HU893408D0 (en) 1991-10-28
US5264425A (en) 1993-11-23
HU208029B (en) 1993-07-28
NZ229403A (en) 1991-02-26
DK286190A (da) 1990-11-30
HUT57237A (en) 1991-11-28
AU3746489A (en) 1990-01-05
AU630359B2 (en) 1992-10-29
IN169470B (it) 1991-10-19
JPH04500377A (ja) 1992-01-23
KR920700232A (ko) 1992-02-19
EP0423151B1 (en) 1993-09-22
EP0423151A1 (en) 1991-04-24
DK286190D0 (da) 1990-11-30
CA1335375C (en) 1995-04-25

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